Synthesis of cyclophosphamide analogs from aminotrideoxy sugars

Cyclophosphamide la is a highly effective and extensively used agent for the treatment of human cancers’. The metabolism, pharmacokinetics, and mechanism of action of la have been the subject of several recent reviews2-5. The activation process of la involves initial hydroxylation by the hepatic cytochrome P450 system to produce one or both isomers ‘9’ of 4-hydroxycyclophosphamide lb. Subsequent formation of aldophosphamide 2 leads to acrolein 3 and phosphoramide mustard’ 4 generally believed to be the ultimate cytotoxic agent that cross-links interstrand DNA’-‘“. Detoxification involves enzymic reactions at C-4 with formation of 4-ketocyclophosphamide 5 or carboxyphosphamide 6 by aldehyde dehydrogenasemediated oxidation. Thus, both formation of active metabolites and detoxification require enzymic reactions at C-4 of the six-membered cyclophosphamide ring. Recent data suggest that acrolein (3), produced by the decomposition of aldophosphamide, is toxic to cultured tumor cells , ‘I but does not play a significant role in the anticancer activity of 1. Acrolein may be responsible for the cardiac and pulmonary toxicities of cyclophosphamide’2 and also for cystitis and renal damage’3,‘4. Since la functions as a prodrug, such pre-activated analogs of la as benzo-annelated cyclophosphamide’5 or 4-hydroxy-(lb), and 4-hydroperoxy-cyclophosphamide”j (lc) have been synthesized both for possible enhancement of activity and for an understanding of the pathways of cyclophosphamide activation and metabolism. By analogy with the well-known strategy in the design of potential anticancer drugs with increased selectivity, attachment of a cyclophosphamide ring system to “carrier” molecules has been reported. This includes steroids for hormonally dependent neoplasm”, amino acids or peptides’*, nucleosides’9-22, and amino